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Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex
Tuberous sclerosis complex (TSC) is a monogenic disorder caused by mutations in either the TSC1 or TSC2 gene, two key regulators of the mechanistic target of the rapamycin complex pathway. Phenotypically, this leads to growth and formation of hamartomas in several organs, including the brain. Subepe...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9560915/ https://www.ncbi.nlm.nih.gov/pubmed/34709498 http://dx.doi.org/10.1007/s10571-021-01157-5 |
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author | Bongaarts, Anika Mijnsbergen, Caroline Anink, Jasper J. Jansen, Floor E. Spliet, Wim G. M. den Dunnen, Wilfred F. A. Coras, Roland Blümcke, Ingmar Paulus, Werner Gruber, Victoria E. Scholl, Theresa Hainfellner, Johannes A. Feucht, Martha Kotulska, Katarzyna Jozwiak, Sergiusz Grajkowska, Wieslawa Buccoliero, Anna Maria Caporalini, Chiara Giordano, Flavio Genitori, Lorenzo Söylemezoğlu, Figen Pimentel, José Jones, David T. W. Scicluna, Brendon P. Schouten-van Meeteren, Antoinette Y. N. Mühlebner, Angelika Mills, James D. Aronica, Eleonora |
author_facet | Bongaarts, Anika Mijnsbergen, Caroline Anink, Jasper J. Jansen, Floor E. Spliet, Wim G. M. den Dunnen, Wilfred F. A. Coras, Roland Blümcke, Ingmar Paulus, Werner Gruber, Victoria E. Scholl, Theresa Hainfellner, Johannes A. Feucht, Martha Kotulska, Katarzyna Jozwiak, Sergiusz Grajkowska, Wieslawa Buccoliero, Anna Maria Caporalini, Chiara Giordano, Flavio Genitori, Lorenzo Söylemezoğlu, Figen Pimentel, José Jones, David T. W. Scicluna, Brendon P. Schouten-van Meeteren, Antoinette Y. N. Mühlebner, Angelika Mills, James D. Aronica, Eleonora |
author_sort | Bongaarts, Anika |
collection | PubMed |
description | Tuberous sclerosis complex (TSC) is a monogenic disorder caused by mutations in either the TSC1 or TSC2 gene, two key regulators of the mechanistic target of the rapamycin complex pathway. Phenotypically, this leads to growth and formation of hamartomas in several organs, including the brain. Subependymal giant cell astrocytomas (SEGAs) are low-grade brain tumors commonly associated with TSC. Recently, gene expression studies provided evidence that the immune system, the MAPK pathway and extracellular matrix organization play an important role in SEGA development. However, the precise mechanisms behind the gene expression changes in SEGA are still largely unknown, providing a potential role for DNA methylation. We investigated the methylation profile of SEGAs using the Illumina Infinium HumanMethylation450 BeadChip (SEGAs n = 42, periventricular control n = 8). The SEGA methylation profile was enriched for the adaptive immune system, T cell activation, leukocyte mediated immunity, extracellular structure organization and the ERK1 & ERK2 cascade. More interestingly, we identified two subgroups in the SEGA methylation data and show that the differentially expressed genes between the two subgroups are related to the MAPK cascade and adaptive immune response. Overall, this study shows that the immune system, the MAPK pathway and extracellular matrix organization are also affected on DNA methylation level, suggesting that therapeutic intervention on DNA level could be useful for these specific pathways in SEGA. Moreover, we identified two subgroups in SEGA that seem to be driven by changes in the adaptive immune response and MAPK pathway and could potentially hold predictive information on target treatment response. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10571-021-01157-5. |
format | Online Article Text |
id | pubmed-9560915 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-95609152022-10-15 Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex Bongaarts, Anika Mijnsbergen, Caroline Anink, Jasper J. Jansen, Floor E. Spliet, Wim G. M. den Dunnen, Wilfred F. A. Coras, Roland Blümcke, Ingmar Paulus, Werner Gruber, Victoria E. Scholl, Theresa Hainfellner, Johannes A. Feucht, Martha Kotulska, Katarzyna Jozwiak, Sergiusz Grajkowska, Wieslawa Buccoliero, Anna Maria Caporalini, Chiara Giordano, Flavio Genitori, Lorenzo Söylemezoğlu, Figen Pimentel, José Jones, David T. W. Scicluna, Brendon P. Schouten-van Meeteren, Antoinette Y. N. Mühlebner, Angelika Mills, James D. Aronica, Eleonora Cell Mol Neurobiol Original Research Tuberous sclerosis complex (TSC) is a monogenic disorder caused by mutations in either the TSC1 or TSC2 gene, two key regulators of the mechanistic target of the rapamycin complex pathway. Phenotypically, this leads to growth and formation of hamartomas in several organs, including the brain. Subependymal giant cell astrocytomas (SEGAs) are low-grade brain tumors commonly associated with TSC. Recently, gene expression studies provided evidence that the immune system, the MAPK pathway and extracellular matrix organization play an important role in SEGA development. However, the precise mechanisms behind the gene expression changes in SEGA are still largely unknown, providing a potential role for DNA methylation. We investigated the methylation profile of SEGAs using the Illumina Infinium HumanMethylation450 BeadChip (SEGAs n = 42, periventricular control n = 8). The SEGA methylation profile was enriched for the adaptive immune system, T cell activation, leukocyte mediated immunity, extracellular structure organization and the ERK1 & ERK2 cascade. More interestingly, we identified two subgroups in the SEGA methylation data and show that the differentially expressed genes between the two subgroups are related to the MAPK cascade and adaptive immune response. Overall, this study shows that the immune system, the MAPK pathway and extracellular matrix organization are also affected on DNA methylation level, suggesting that therapeutic intervention on DNA level could be useful for these specific pathways in SEGA. Moreover, we identified two subgroups in SEGA that seem to be driven by changes in the adaptive immune response and MAPK pathway and could potentially hold predictive information on target treatment response. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10571-021-01157-5. Springer US 2021-10-28 2022 /pmc/articles/PMC9560915/ /pubmed/34709498 http://dx.doi.org/10.1007/s10571-021-01157-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Research Bongaarts, Anika Mijnsbergen, Caroline Anink, Jasper J. Jansen, Floor E. Spliet, Wim G. M. den Dunnen, Wilfred F. A. Coras, Roland Blümcke, Ingmar Paulus, Werner Gruber, Victoria E. Scholl, Theresa Hainfellner, Johannes A. Feucht, Martha Kotulska, Katarzyna Jozwiak, Sergiusz Grajkowska, Wieslawa Buccoliero, Anna Maria Caporalini, Chiara Giordano, Flavio Genitori, Lorenzo Söylemezoğlu, Figen Pimentel, José Jones, David T. W. Scicluna, Brendon P. Schouten-van Meeteren, Antoinette Y. N. Mühlebner, Angelika Mills, James D. Aronica, Eleonora Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex |
title | Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex |
title_full | Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex |
title_fullStr | Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex |
title_full_unstemmed | Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex |
title_short | Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex |
title_sort | distinct dna methylation patterns of subependymal giant cell astrocytomas in tuberous sclerosis complex |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9560915/ https://www.ncbi.nlm.nih.gov/pubmed/34709498 http://dx.doi.org/10.1007/s10571-021-01157-5 |
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